Piecing Together the Puzzle of Cutaneous Mosaicism

Piecing together the puzzle of cutaneous mosaicism

Amy S. Paller

J Clin Invest. 2004;114(10):1407-1409. https://doi.org/10.1172/JCI23580.

Commentary

Autosomal dominant disorders of the skin may present in a pattern following the lines of embryologic development of the ectoderm. In these cases, the surrounding skin is normal, and molecular studies have shown that the causative mutation is confined to the affected ectodermal tissue (type 1 mosaicism). Rarely, an individual shows skin lesions that follow the pattern of type 1 mosaicism, but the rest of the skin shows a milder form of the disorder (type 2 mosaicism). A new study provides the molecular basis for type 2 mosaicism .

Find the latest version: https://jci.me/23580/pdf commentaries Piecing together the puzzle of cutaneous mosaicism Amy S. Paller

Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Autosomal dominant disorders of the skin may present in a pattern following, and erythema in addition to the sym- ing the lines of embryologic development of the ectoderm. In these cases, metrically distributed milder plaques of the surrounding skin is normal, and molecular studies have shown that erythema and crusting (16). the causative mutation is confined to the affected ectodermal tissue (type 1 mosaicism). Rarely, an individual shows skin lesions that follow the pat- Providing a molecular mechanism tern of type 1 mosaicism, but the rest of the skin shows a milder form of the to explain type 2 mosaicism disorder (type 2 mosaicism). A new study provides the molecular basis for In this issue of the JCI, Poblete-Gutiérrez type 2 mosaicism (see the related article beginning on page 1467). et al. (17) provide evidence of the molecular basis of type 2 mosaicism in Hailey- More than a century ago, the lines of The molecular basis for somatic mosa- Hailey disease. This autosomal domi- Blaschko were first described by German icism in several other epidermal disorders nant disorder, characterized by abnormal dermatologist Alfred Blaschko, based on that follow Blaschko’s lines has since been keratinocyte differentiation, results from the observation of patterned skin lesions established, providing further evidence mutations in ATP2C1, which encodes the that were linear on the extremities, S-shaped that Blaschko’s lines represent pathways calcium pump protein ATPase, Ca2+ trans- on the anterior trunk, and V-shaped on the of ectodermal embryonic development porting, type 2C, member 1. In contrast to back (1) (Figure 1). Blaschko’s lines are (5–8). Mosaicism has also been shown to many autosomal dominant disorders of thought to trace pathways of ectodermal reverse clinical phenotypes, particularly in the skin in which lesions are widespread cell development. Happle has championed patients with forms of the group of gen- and, upon clinical examination, no skin the concept that the cutaneous lesions fol- eralized blistering disorders known as epi- appears to be spared, the red, crusted lowing Blaschko’s lines are manifestations dermolysis bullosa (9, 10). The localized plaques of Hailey-Hailey disease tend to of somatic mosaicism (2). genetic correction of keratin 14 in basal be symmetrically distributed primarily at Mosaicism results when a postzygotic keratinocytes in some of these patients intertriginous areas, where opposing skin mutation occurs in gonadal (germline leads to progressive clinical improvement, surfaces may touch and rub, such as skin mosaicism) or other (somatic mosaicism) which reflects the selective advantage folds of the groin, underarm, and breast. cells, leading to an organism with two or of normal versus lesional proliferating The patient studied by Poblete-Gutiérrez more genetically different populations keratinocytes that has recently been shown et al. developed widely distributed, severe- of cells that originate from a genetically in mouse models (11). ly erythematous, and crusted plaques homogeneous zygote. In most cases of along Blaschko’s lines on the left side of clinical mosaicism, the linear patterns of Two types of mosaicism her body (16, 17). In contrast to the typi- abnormal skin are surrounded by normal Several patients with autosomal domi- cal onset of plaques largely confined to skin; this has been termed type 1 mosa- nant disorders of the skin have now been intertriginous areas in late childhood or icism. The first demonstration that clini- described as showing diffuse cutaneous young adulthood, these extensive plaques cal mosaicism in skin along Blaschko’s involvement with their genetic disease were first noted when the patient was 3 lines correlates perfectly with keratinocyte but linear patterns of exacerbation of the months of age (17). genetic mosaicism was based on the dis- skin disorder that follow Blaschko’s lines, Keratinocytes isolated by laser discovery in 1994 of keratin 10 mutations in although this is a rare occurrence. This section or cultured after biopsy of lesional skin, but not in clinically normal type 2 form of mosaicism has been seen these severely affected areas harbored a skin, of patients with a form of epidermal (a) in patients with superficial actinic homozygous genetic defect in ATP2C1, nevi that histologically shows epidermal porokeratosis with streaks of thick linear while keratinocytes isolated from other lysis and marked stratum corneum thick- porokeratosis (12, 13); (b) in those with sites showed the heterozygous defect. ening (3). These are characteristic features tumor syndromes in which large numbers In this patient with type 2 mosaicism, of the skin of patients with epidermolytic of cutaneous tumors are confined to a seg- the loss of heterozygosity resulted from hyperkeratosis, a genetic condition with mental or linear distribution, e.g., dermal mutation and loss of the paternal allele. diffuse bilateral involvement that is known neurofibromas in neurofibromatosis type The localized genetic change from one to result from mutations in keratin 10 (4). 1 (14), leiomyomas in multiple cutane- normal allele and one abnormal allele ous and uterine leiomyomatosis (15), and (heterozygous state of a typical individual hamartomas of the tongue in tuberous with Hailey-Hailey disease) to only the Conflict of interest: The author has declared that no conflict of interest exists. sclerosis (14); and (c) in individuals with abnormal allele (loss of heterozygosity) Citation for this article: J. Clin. Invest. 114:1407–1409 Hailey-Hailey disease, characterized by gave the patient a double dose of the (2004). doi:10.1172/JCI200423580. segmental areas of severe crusting, ooz- mutant gene in severely affected areas,

The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 10 November 2004 1407 commentaries

Figure 1 The lines of Blaschko, originally described in 1901, are thought to trace the pathway of ectodermal cell development. These lines are linear on the extremities, S-shaped on the anterior trunk, and V-shaped on the back. Epidermal nevi are examples of cutaneous mosaicism in which the localized thickening of the epidermis is patterned along the lines of Blaschko. This figure illustrates several forms of epidermal nevi and the correlation of their orientation with the lines of Blaschko. A shows two verrucous (or keratinocytic) forms of epidermal nevus on the anterior (upper image) and anterolateral (lower image) regions of the trunk that correlate nicely with the lines of Blaschko, shown schematically. Similarly, B shows epidermal nevi of the epidermolytic hyperkeratotic type (upper image) in a curvilinear configuration and an inflammatory linear verrucous form of epidermal nevus on the leg (lower image). The molecular mechanism underlying the defect is known for only one of these clinical manifestations, the epidermolytic hyperkeratotic form of epidermal nevus. The 6-year-old girl shown in B showed a missense mutation in keratin 10 in cultured keratinocytes from lesional, but not normal-appearing, skin.

leading to the patterned disease exacerba- as early investigations in the understand- ous mosaicism with inducible localized tion along Blaschko’s lines. A variety of ing of gene mosaicism. One continuing mutations may allow us to correlate the mutational events may occur that lead to area of investigation is the relationship extent and distribution of mosaic mani- loss of the normal allele (hemizygosity) or of the extent of cutaneous manifesta- festations with the time at which these duplication of the mutant chromosome tion of mosaicism to the risk of germline postzygotic mutations occur and to cor- (homozygosity), among them point muta- involvement, which could lead to a wide- relate this timing with ectodermal versus tion, localized gene conversion, mitotic spread skin disorder in offspring of a par- mesodermal development. recombination, deletion, and nondisjunc- ent with type 1 mosaicism. Keratinocyte Importantly, even less is known about tion. In the patient with type 2 mosaicism mutations with an earlier time of onset the embryologic development and mosa- and Hailey-Hailey disease, Poblete-Gutiér- during the postzygotic period are theo- icism of nonectodermal structures. Two rez et al. demonstrate loss of the paternal rized to be associated with a lower risk of examples of possible dermal mosaicism allele with duplication of the mutated germline mutation, and more extensive are morphea (a disorder of localized der- maternal allele, probably by postzygotic skin involvement is thought to be associ- mal sclerosis) and focal dermal hypoplasia mitotic recombination (17). ated with a higher risk. In type 1 mosa- (characterized by streaks of dermal tis- The novel discovery of the basis for type 2 icism, up to 50% of peripheral blood leu- sue hypoplasia, often in association with mosaicism contributes to our under- kocytes may harbor the mutation; given streaks in the metaphyses of long bones). standing of gene mosaicism as well as of the mesodermal origin of both blood cells However, the underlying genetic basis for embryologic development of the ectoderm and germline cells, one might surmise these disorders remains unknown, pre- along the defined lines of Blaschko. How- that a higher ratio of mutant to normal venting the confirmation of mutation ever, demonstration of the correlation of genomic DNA would be associated with a within cells of mesodermal origin. Several mosaic genotype and phenotype in these higher risk of germline involvement, but studies have clearly demonstrated that the studies and in the studies of the molecular this possibility has not been assessed. Use genotypes of keratinocytes and underly- basis for type 1 mosaicism should be seen of engineered mouse models of cutane- ing fibroblasts do not correlate in mosaic

1408 The Journal of Clinical Investigation http://www.jci.org Volume 114 Number 10 November 2004 commentaries skin conditions, confirming the different Braunmuller. Vienna, Austria and Leipzig, Germany. Novel mechanism of revertant mosaicism in Dowl- 2. Happle, R. 1993. Mosaicism in human skin. Under- ing-Meara epidermolysis bullosa simplex. J. Invest. developmental patterns of ectoderm and standing the patterns and mechanisms. Arch. Dermatol. 122:73–77. mesoderm (3). The disparate development Dermatol. 129:1460–1470. 11. Arin, M.J., Longley, M.A., Wang, X.J., and Roop, of ectodermal and mesodermal structures 3. Paller, A.S., et al. 1994. Genetic and clinical mosa- D.R. 2001. Focal activation of a mutant allele emphasizes the need to study affected tis- icism in a type of epidermal nevus. N. Engl. J. Med. defines the role of stem cells in mosaic skin disor- 331:1408–1415. ders. J. Cell Biol. 152:645–649. sues when seeking evidence of gene mosa- 4. Rothnagel, J.A., et al. 1992. Mutations in the rod 12. Happle, R. 1991. Somatic recombination may icism. Patterned epidermal and dermal domains of keratins 1 and 10 in epidermolytic explain linear porokeratosis associated with dis- mosaic disorders (such as morphea and hyperkeratosis. Science. 257:1128–1130. seminated superficial actinic porokeratosis. Am. J. 5. Colman, S.D., Rasmussen, S.A., Ho, V.T., Aberna- Med. Genet. 39:237. focal dermal hypoplasia) provide an ideal thy, C.R., and Wallace, M.R. 1996. Somatic mosa- 13. Happle, R. 1996. Segmental forms of autosomal focus for future investigations that will icism in a patient with neurofibromatosis type 1. dominant skin disorders: different types of sever- elucidate the mechanisms of embryolog- Am. J. Hum. Genet. 58:484–490. ity reflect different states of zygosity. Am. J. Med. 6. Munro, C.S., and Wilkie, A.O. 1998. Epidermal Genet. 66:241–242. ic development of both ectodermal and mosaicism producing localised acne: somatic 14. Itin, P.H., and Buechner, S.A. 1999. Segmental mesodermal tissues. mutation in FGFR2. Lancet. 352:704–705. forms of autosomal dominant skin disorders: the 7. Sakuntabhai, A., Dhitavat, J., Burge, S., and Hov- puzzle of mosaicism. Am. J. Med. Genet. 85:351–354. nanian, A. 2000. Mosaicism for ATP2A2 mutations 15. Smith, C.G., Glaser, D.A., and Leonardi, C. 1998. Address correspondence to: Amy S. causes segmental Darier’s disease. J. Invest. Dermatol. Zosteriform multiple leiomyomas. J. Am. Acad. Paller, Department of Dermatology, 645 115:1144–1147. Dermatol. 38:272–273. North Michigan Avenue, Suite 520, Chi- 8. Terrinoni, A., et al. 2000. A mutation in the V1 16. Vakilzadeh, F., and Kolde, G. 1985. Relapsing cago, Illinois 60611, USA. Phone: (312) domain of K16 is responsible for unilateral pal- linear acantholytic dermatosis. Br. J. Dermatol. moplantar verrucous nevus. J. Invest. Dermatol. 112:349–355. 695-0197; Fax: (312) 695-0664: E-mail: 114:1136–1140. 17. Poblete-Gutiérrez, P., et al. 2004. Allelic loss under- [email protected]. 9. Jonkman, M.F., et al. 1997. Revertant mosaicism in lies type 2 segmental Hailey-Hailey disease, pro- epidermolysis bullosa caused by mitotic gene con- viding molecular confirmation of a novel genetic 1. Blaschko, A. 1901. Die Nervenverteilung in der Haut in version. Cell. 88:543–551. concept. J. Clin. Invest. 114:1467–1474. doi:10.1172/ ihrer Beziehung zu den Erkrankungen der Haut. Wilhelm 10. Smith, F.J., Morley, S.M., and McLean, W.H. 2004. JCI200421791. The multiple causes of human SCID Rebecca H. Buckley

Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.

SCID, a syndrome characterized by the absence of T cells and adaptive immu- ucts of 3 of these mutated genes are com- nity, can result from mutations in multiple genes that encode components of ponents of cytokine receptors (the IL-2 the immune system. Three such components are cytokine receptor chains or receptor γ chain that is also shared with signaling molecules, five are needed for antigen receptor development, one 5 other cytokine receptors [IL-4R, IL-7R, is adenosine deaminase — a purine salvage pathway enzyme, and the last is a IL-9R, IL-15R, and IL-21R], JAK3, the pri- phosphatase, CD45. In this issue of the JCI, a report describes how complete mary signal transducer from the common deficiency of the CD3ε chain of the T cell antigen receptor/CD3 complex γ chain, and the α chain of the IL-7 recep- causes human SCID (see the related article beginning on page 1512). tor); the products of 5 more genes (RAG1, RAG2, Artemis, CD3δ, and CD3ε) are nec- Human SCID was first reported by Glan- SCID, adenosine deaminase deficiency, was essary for antigen-receptor development; zmann and Riniker in 1950 (1). Swiss reported in 1972 (2). However, it was not infants with the condition were profound- until 21 years later, in 1993, that a second ly lymphopenic and died of infection fundamental cause of the condition was Table 1 before their first or second birthdays. In found, i.e., the molecular basis of X-linked Ten abnormal genes in human SCID the ensuing years, differences were noted human SCID (3, 4). Over the past 11 years, in inheritance patterns for SCID. This remarkable progress has been made in elu- Cytokine-receptor genes indicated that there was more than one cidating several other causes of this syn- IL-2RG cause for this fatal syndrome character- drome (5). Advances in molecular biology JAK3 ized by an absence of T cells and all adap- and the Human Genome Project as well IL-7Rα tive immunity. In many families there was as increased knowledge of various com- Antigen-receptor genes an X-linked recessive mode of inheritance ponents of the immune system through RAG1 while in others an autosomal recessive studies of mutant mice and humans with RAG2 mode of inheritance was observed. The genetically determined immunodeficien- Artemis first discovered molecular cause of human cies have all contributed to this under- CD3δ standing. It is now known that SCID can CD3ε be caused in humans by mutations in at Conflict of interest: The author has declared that no Other genes conflict of interest exists. least 10 different genes (Table 1) (6–11), ADA Citation for this article: J. Clin. Invest. 114:1409–1411 and the likelihood is that there are other CD45 (2004). doi:10.1172/JCI200423571. causes yet to be discovered. The gene prod-

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